Project Summary Beyond its well-established role in maintaining systemic calcium homeostasis, a substantial and growing body of research points to the physiological importance of vitamin D as a neuroactive steroid. Despite such data, experimental evidence of vitamin D?s direct effects on brain function in humans is all but lacking. This gap hinders both our understanding of the role of vitamin D in human behavior as well as its therapeutic potential for neuropsychiatric disorders (i.e., including and beyond vitamin deficiency states). Recent preclinical (rodent) research by members of our group demonstrate important modulatory effects of the physiologically active form of vitamin D, calcitriol, on mesolimbic dopamine (DA) systems. These data demonstrate: 1) expression of VDRs in tyrosine hydroxylase (TH) containing DA neurons of the ventral tegmental area (VTA) and dopamine D2/3 receptor-expressing cells in striatum/nucleus accumbens (NAc); and they further show that acute calcitriol administration: 2) increases TH expression in VTA DA neurons; 3) increases dopamine D2/3 receptor mRNA in NAc; 4) increases microdialysate (?tonic?) and cyclic voltammetry (?phasic?) measures of striatal DA release (including in response to amphetamine); 5) increases amphetamine- induced locomotion, and 6) decreases drug (amphetamine) self-administration in animals. If also true of humans, such effects would be of considerable clinical importance, given the number of human behaviors (e.g., learning, memory, reward, affective and information processing, etc.) mediated by mesolimbic/subcortical DA circuits and the number of disorders (e.g., attention deficit hyperactivity disorder, addiction, depression, Parkinson?s disease, etc.) in which mesolimbic/subcortical DA deficits have been implicated. The current exploratory/developmental R01 seeks to test this hypothesis directly in healthy humans. Specifically, we will assess subcortical DA function (in vivo DA release) in 20 medically and psychiatrically healthy (vitamin D sufficient) humans using high-resolution 11C-PHNO PET. Specifically, subjects (N=20) will participate in four 11C-PHNO PET sessions, including two pairs of pre- and post-amphetamine (0.3 mg/kg PO) scans of D2/3 receptor availability (BPND) conducted on two separate days two weeks apart. Scan days will be preceded by placebo/active calcitriol (3.0 g) pretreatment per a fully randomized, double-blind, counterbalanced, placebo- controlled, within-subject design. We hypothesize that calcitriol will increase amphetamine-stimulated DA release as reflected by greater reductions in ventral striatal D2/3 receptor availability (?BPND) on active vs. placebo days and that such changes will be accompanied by parallel improvements in DA-mediated behaviors.